The insulin-like growth factor receptor (IGF-IR) is composed of two types of subunits: an alpha subunit (a 130-135 kDa protein that is entirely extracellular and functions in ligand binding) and a beta subunit (a 95-kDa transmembrane protein, with transmembrane and cytoplasmic domains). The IGF-IR binds insulin-like growth factor I (IGF-I), or IGF-II or insulin at supraphysiological concentrations. The IGF-IR belongs to the family of tyrosine kinase growth factor receptors (Ullrich et al., 1990), and is structurally similar to the insulin receptor (Ullrich et al., 1986).
The IGF-IR is initially synthesized as a single chain proreceptor polypeptide, which is processed by glycosylation, proteolytic cleavage, and covalent bonding to assemble into a mature 460 kDa heterotetramer comprising two alpha-subunits and two beta-subunits. The beta subunit(s) possesses ligand-activated tyrosine kinase activity. This activity is implicated in the signaling pathways mediating ligand action which involve autophosphorylation of the beta-subunit and phosphorylation of IGF-IR substrates.
There is considerable evidence for a role for the IGF-IR in the maintenance of tumor cells in vitro. IGF-IR levels are elevated in tumors of lung (Kaiser et al., 1993; Moody et al., 1993; Macaulay et al., 1990), breast (Pollak et al., 1987; Foekens et al., 1989; Cullen et al., 1990; Arteaga et al., 1989), prostate and colon (Remade-Bonnet et al., 1992; Guo et al., 1992). For a review of the potential role of IGF-IR and the growth of a variety of human tumors see Macaulay, 1992.